Nitrogenous heterocyclic derivatives and their application in drugs
The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, IPF, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.
1. A compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof,
wherein, each of Q 1 and Q 2 is independently CH;
X is N;
J is —CH 2 —;
each R 1 is independently —Y—R 5 , wherein each Y is independently —O—, —(CH 2 ) m —O—, —(CH 2 ) m —N(R 6 )—, —N(R 6 )—, or —(CH 2 ) m —;
each R 1a is independently H, F, Cl, Br, I, cyano, hydroxy, amino, carboxy, alkyl, haloalkyl, alkoxy, alkylamino, alkylthio, alkenyl, alkynyl, nitro, mercapto, hydroxyalkoxy, hydroxyalkyl, aminoalkoxy, alkyl-O—C(═O)—, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, aryloxy, heteroaryloxy, haloalkoxy or cycloalkylalkyl;
each of R 2 and R 3 is independently H, F, Cl, Br, I, cyano, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, hydroxyalkoxy, hydroxyalkyl, aminoalkoxy, haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl;
each R 4 is independently H, hydroxy, carboxy, amino, F, Cl, Br, I, cyano, nitro, mercapto, alkyl, haloalkyl, alkoxy, alkylamino, alkylthio, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl;
each R 5 is independently bridged heterobicyclyl, bridged bicyclyl, fused bicyclyl, fused heterobicyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl, wherein the aryl is substituted with one or more substituents independently selected from F, Cl, Br, I, alkyl —O—C(═O)—, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, nitro, amino, alkylamino, mercapto, alkylthio, aryl, aryloxy, heteroaryl, heteroaryloxy and haloalkoxy;
each R 6 is independently H, hydroxy, amino, alkyl, haloalkyl, alkoxy, alkylamino, alkylthio, aryl, arylalkyl or heteroaryl;
each t is independently 0, 1 or 2;
each m is independently 1, 2, 3 or 4;
each of n and p is independently 0, 1, 2, 3 or 4; and
k is 1, 2, 3 or 4;
wherein each of —(CH 2 ) m —O—, —(CH 2 ) m —N(R 6 )—, —N(R 6 )—, —(CH 2 ) m —, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, hydroxyalkoxy, hydroxyalkyl, aminoalkoxy, alkyl-O—C(═O)—, aryl, aryloxy, heteroaryloxy, haloalkoxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, bridged heterobicyclyl, bridged bicyclyl, fused bicyclyl, fused heterobicyclyl, alkylamino and alkylthio is independently and optionally substituted with one or more substituents independently selected from oxo (═O), F, Cl, Br, I, alkyl —O—C(═O)—, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, nitro, amino, alkylamino, mercapto, alkylthio, aryl, aryloxy, heteroaryl, heteroaryloxy and haloalkoxy.
2. The compound according to claim 1 , wherein
each R 5 is independently C 5-12 bridged heterobicyclyl, C 5-12 bridged bicyclyl, C 5-12 fused bicyclyl, C 5-12 fused heterobicyclyl, C 6-10 aryl, C 6-10 aryl-C 1-4 -alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl-C 1-4 -alkyl, C 2-10 heterocyclyl, C 2-10 heterocyclyl-C 1-4 -alkyl, C 3-10 cycloalkyl or C 3-10 cycloalkyl-C 1-4 -alkyl, wherein each the aryl is substituted with one or more substituents independently selected from F, Cl, Br, I, C 1-4 alkyl-O—C(═O)—, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, cyano, nitro, amino, C 1-4 alkylamino, mercapto, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryloxy, C 1-9 heteroaryl, C 1-9 heteroaryloxy and C 1-4 haloalkoxy; and
each R 6 is independently H, hydroxy, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryl-C 1-4 -alkyl or C 1-9 heteroaryl;
wherein each of C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 5-12 bridged heterobicyclyl, C 5-12 bridged bicyclyl, C 5-12 fused bicyclyl, C 5-12 fused heterobicyclyl, C 6-10 aryl, C 6-10 aryl-C 1-4 -alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl-C 1-4 -alkyl, C 2-10 heterocyclyl, C 2-10 heterocyclyl-C 1-4 -alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 -alkyl, C 1-4 alkylamino and C 1-4 alkylthio is independently and optionally substituted with one or more substituents independently selected from oxo (═O), F, Cl, Br, I, C 1-4 alkyl-O—C(═O)—, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, cyano, nitro, amino, C 1-4 alkylamino, mercapto, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryloxy, C 1-9 heteroaryl, C 1-9 heteroaryloxy and C 1-4 haloalkoxy.
3. The compound according to claim 1 , wherein:
each R 1a is independently H, F, Cl, Br, I, cyano, hydroxy, amino, carboxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, nitro, mercapto, C 1-4 hydroxyalkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkoxy, C 1-4 alkyl-O—C(═O)—, C 6-10 aryl, C 6-10 aryl-C 1-4 -alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl-C 1-4 -alkyl, C 2-10 heterocyclyl, C 2-10 heterocyclyl-C 1-4 -alkyl, C 3-10 cycloalkyl, C 6-10 aryloxy, C 1-9 heteroaryloxy, C 1-4 haloalkoxy or C 3-10 cycloalkyl-C 1-4 -alkyl;
each of R 2 and R 3 is independently H, F, Cl, Br, I, cyano, carboxy, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkoxy, C 1-6 haloalkoxy, C 6-10 aryl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl-C 1-6 -alkyl, C 2-10 heterocyclyl, C 2-10 heterocyclyl-C 1-6 -alkyl, C 3-10 cycloalkyl or C 3-10 cycloalkyl-C 1-6 -alkyl; and
each R 4 is independently H, hydroxy, carboxyl, amino, F, Cl, Br, I, cyano, nitro, mercapto, C 1-4 alkyl, C 1-6 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryl-C 1-4 -alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl-C 1-6 -alkyl, C 2-10 heterocyclyl, C 2-10 heterocyclyl-C 1-6 -alkyl, C 3-10 cycloalkyl or C 3-10 cycloalkyl-C 1-6 -alkyl.
4. The compound according to claim 1 having formula (II), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt or a prodrug thereof,
wherein, each of Q 1 and Q 2 is independently CH;
J is —CH 2 —; and
Y is —O—, —(CH 2 ) m —O—, —(CH 2 ) m —N(R 6 )—, —N(R 6 )— or —(CH 2 ) m —.
5. The compound according to claim 1 , wherein,
each Y is independently —O—, —(CH 2 ) m —O—, —(CH 2 ) m —N(R 6 )—, —N(R 6 )— or —(CH 2 ) m —;
each R 5 is independently
wherein, each E 1 , E 3 and E 4 is independently N or CR 7 ;
E 2 is N;
each T, T 1 and T 2 is independently —NR 8 —, —O—, —S— or —CR 7 R 7a —;
each R 7 and R 7a is independently H, F, Cl, Br, I, C 1-4 alkyl-O—C(═O)—, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, cyano, nitro, amino, C 1-4 alkylamino, mercapto, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryloxy, C 1-9 heteroaryl, C 1-9 heteroaryloxy or C 1-4 haloalkoxy;
wherein, each R 5 is independently and optionally substituted with one or more substituents independently selected from oxo (═O), F, Cl, Br, I, C 1-4 alkyl —O—C(═O)—, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, cyano, nitro, amino, C 1-4 alkylamino, mercapto, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryloxy, C 1-9 heteroaryl, C 1-9 heteroaryloxy and C 1-4 haloalkoxy;
each R 6 is independently H, hydroxy, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryl-C 1-4 -alkyl or C 1-9 heteroaryl; and
each R 8 is independently H, C 1-4 alkyl-O—C(═O)—, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, amino, C 1-4 alkylamino, C 1-4 alkylthio, C 6-10 aryl or C 1-9 heteroaryl.
6. The compound according to claim 1 , wherein,
each R 5 is independently
wherein, each R 9 is independently H, oxo (═O), F, Cl, Br, I, C 1-4 alkyl-O—C(═O)—, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, cyano, nitro, amino, C 1-4 alkylamino, mercapto, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryloxy, C 1-9 heteroaryl, C 1-9 heteroaryloxy or C 1-4 haloalkyloxy; and
each q is independently 0, 1, 2, 3, 4, 5, 6 or 7.
7. The compound according to claim 6 , wherein,
each R 9 is independently H, oxo (═O), F, Cl, Br, I, methyl-O—C(═O)—, ethyl-O—C(═O)—, propyl-O—C(═O)—, butyl-O—C(═O)—, tert-butyl —O—C(═O)—, isopropyl-O—C(═O)—, methyl, ethyl, propyl, butyl, tert-butyl, isopropyl, ethenyl, 3-propenyl, propenyl, C 2-4 alkynyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, chloromethyl, trifluoroethyl, 1-fluoroethyl, cyano, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, mercapto, methylthio, ethylthio, propylthio, C 6-10 aryl, phenoxy, C 1-9 heteroaryl, C 1-9 heteroaryloxy, trifluoroethoxy or trifluoromethoxy.
8. The compound according to claim 1 , wherein,
each R 1a is independently H, F, Cl, Br, I, cyano, hydroxy, amino, carboxyl, methyl, ethyl, propyl, butyl, tert-butyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloroethyl, methoxy, propoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, methylthio, ethylthio, C 2-4 alkenyl, C 2-4 alkynyl, nitro, mercapto, C 1-4 hydroxyalkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkoxy, C 1-4 alkyl-O—C(═O)— or phenyl;
each of R 2 and R 3 is independently H, F, Cl, Br, I, cyano, carboxyl, hydroxy, methyl, ethyl, propyl, butyl, tert-butyl, trifluoromethyl, chloromethyl, trifluoroethyl, 1-chloroethyl, methoxy, ethoxy, propoxy, C 1-4 hydroxyalkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkoxy, trifluoromethoxy, 1-chloroethoxy, phenyl or phenyl-C 1-4 -alkyl; and
each R 4 is independently H, F, Cl, Br, I, cyano, carboxyl, hydroxy, methyl, ethyl, propyl, butyl, tert-butyl, trifluoromethyl, chloromethyl, trifluoroethyl, 1-chloroethyl, methoxy, ethoxy, propoxy, C 1-4 hydroxyalkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkoxy, trifluoromethoxy, 1-chloroethoxy, phenyl or phenyl-C 1-4 -alkyl.
9. A Compound having one of the following structures:
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a hydrate, a ester, or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising the compound according to claim 1 , and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
11. A method of, managing, treating or lessening the severity of tissue or organ fibrosis in a patient comprising administering to the patient with the compound according to claim 1 .
12. The method according to claim 11 , wherein the tissue or organ fibrosis is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, IPF, peritoneum fibrosis, myocardial fibrosis, dermatofibrosis, post-surgery adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, dermatosclerosis, multiple sclerosis, pancreatic fibrosis, liver cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, or vascular fibrosis.
13. A method of, managing, treating or lessening the severity of tissue or organ fibrosis in a patient comprising administering to the patient with the pharmaceutical composition according to claim 10 .
14. The method according to claim 13 , wherein the tissue or organ fibrosis is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, IPF, peritoneum fibrosis, myocardial fibrosis, dermatofibrosis, post-surgery adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, dermatosclerosis, multiple sclerosis, pancreatic fibrosis, liver cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, or vascular fibrosis.
15. The compound according to claim 1 , wherein,
each Y is independently —O—, —(CH 2 ) m —O—, —(CH 2 ) m —N(R 6 )—, —N(R 6 )— or —(CH 2 ) m —;
each R 5 is independently
wherein, each E 1 and E 3 is independently N or CR 7 ;
R 7 is H, F, Cl, Br, I, C 1-4 alkyl-O—C(═O)—, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, cyano, nitro, amino, C 1-4 alkylamino, mercapto, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryloxy, C 1-9 heteroaryl, C 1-9 heteroaryloxy or C 1-4 haloalkoxy;
wherein, each R 5 is independently substituted with one or more substituents independently selected from F, Cl, Br, I, C 1-4 alkyl —O—C(═O)—, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, cyano, nitro, amino, C 1-4 alkylamino, mercapto, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryloxy, C 1-9 heteroaryl, C 1-9 heteroaryloxy and C 1-4 haloalkoxy;
each R 6 is independently H, hydroxy, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryl-C 1-4 -alkyl or C 1-9 heteroaryl; and
each m is independently 1, 2, 3 or 4.
16. The compound according to claim 1 , wherein,
each R 5 is independently
wherein, each R 9 is independently F, Cl, Br, I, C 1-4 alkyl-O—C(═O)—, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, cyano, nitro, amino, C 1-4 alkylamino, mercapto, C 1-4 alkylthio, C 6-10 aryl, C 6-10 aryloxy, C 1-9 heteroaryl, C 1-9 heteroaryloxy or C 1-4 haloalkyloxy; and
each q is independently 1, 2, 3, 4, 5, 6 or 7.